Department of Developmental & Molecular Biology

Fajun Yang's Laboratory

Dr. Fajun Yang

Transcriptional Regulation of Lipid Homeostasis

The sterol regulatory element binding protein (SREBP) family of basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors are critical regulators of both lipid and cholesterol homeostasis. SREBP proteins are synthesized as inactive precursors that are tethered to the endoplasmic reticulum (ER) membrane. In response to decreased cellular levels of sterols, SREBP precursors are proteolytically processed to mature forms that migrate into the nucleus and activate transcription of target genes, such as fatty acid synthase and the LDL receptor. Our lab is interested in understanding how SREBP-mediated transcription is regulated. Co-activators, including the histone acetyltransferases CBP/p300 and the Mediator complex, are involved in activating transcription of SREBP target genes. The Mediator is a multi-subunit protein complex. Biochemical and genetic approaches are being taken to further study the role of the Mediator subunits in SREBP-mediated transcription. In addition, molecular mechanisms of SREBP degradation during fasting are being studied. Recently, we have observed that the NAD-dependent histone deacetylase SIRT1 orthologs negatively control the expression of SREBP target genes in human cells, and in C. elegans and Drosophila, consistent with the inverse relationship between SIRT1 and SREBP protein levels during fasting. SREBP protein stability can be regulated by acetylation. Thus, SIRT1 may play a key role in mediating down-regulation of SREBP proteins during fasting. We have also found that SIRT1 is physically and functionally associated with multi-functional protein complexes that are known to regulate Notch signaling. We are currently studying the functions of SIRT1 complexes in controlling Notch signaling in the process of adipogenesis. With the ultimate goal of identifying targets for preventing or treating metabolic syndrome, the aim of our research is to advance our knowledge of how lipid homeostasis is regulated at the molecular levels.